ECOADAPT Résumé de rapport

Understanding the adaptation of bacteria to the pressure imposed by the immune system unravels their potential to become pathogenic. The antagonistic interaction between bacteria and the host immune system is a key factor in nature that had not been previously studied in the context of experimental evolution. The extent to which different adaptations to this important biotic factor can emerge and how fast they can happen are key questions for our understanding of the transition between commensalism and pathogenesis. We have used experimental evolution, an extraordinarily powerful methodology to study adaptation in real time, to determine the speed and the most likely evolutionary paths of bacterial adaptation to the primary defence cells of the host immune system - macrophages. Since Escherichia coli is both a commensal but also a versatile pathogen we have used this bacteria as an experimental model. We show how dramatically fast non-virulent bacteria can evolve phenotypes which are characteristic of pathogenic bacteria and which make it more virulent. The two main types of adaptations found here, through in vitro evolution, resemble those of clinical infections where natural in vivo evolution occurs. We have dissected the genetic basis of the evolved virulent strains at the whole genome level, and discovered a repeatable evolutionary scenario. The process of mutation and selection studied exhibits complex temporal population dynamics. We have developed novel mathematical models to help understanding the dynamical nature of the pathoadaptive evolutionary process. We also extended theoretical models of adaptation beyond their classical simplistic assumptions to be able to explain and integrate major patterns observed in data from many published experiments. We found that some of the virulent bacterial clones, evolved in the presence of macrophages, exhibit increased resistance to certain antibiotics but also increased sensitivity to specific antibiotics, a phenotype which can be used to control their frequency within hosts. Furthermore we found that many mutations that confer resistance to commonly used antibiotics provide a survival advantage for bacteria in the intracellular environment of macrophages. These findings have important implications for the evolution of resistance in the context of infections. We have taken our study further to show that the adaptations evolved in vitro have important consequences in vivo, in one of the most relevant ecosystems for the bacteria, the mammalian gut. In doing so, we demonstrated that bacteria adaptation in the gut is very rapid and characterized by a complex evolutionary dynamics where the co-occurrence of many different strains of the same species is pervasive - this phenomenon is called clonal interference. We have therefore provided the first direct evidence of the importance of this well described theoretical phenomenon, in a natural ecosystem. Overall these results reveal the richness of the microbiota and have important consequences for our understanding of health and disease scenarios related with the microbiome. The project integrates methodologies from Evolutionary Biology, Microbiology and Immunology, and its findings have impact in all the three fields. ECOADAPT contributed to the success of the thesis of 4 PhD students and the research career of several Post-docs. It also contributed to the formation of research technicians, which currently hold PhD fellowships in other research institutions abroad (e.g. Brazil and France).